联合神经氨酸酶和聚合酶抑制剂治疗感染流感病毒的裸鼠。
Combination Therapy With Neuraminidase and Polymerase Inhibitors in Nude Mice Infected With Influenza Virus.
机构信息
Division of Virology, Department of Microbiology and Immunology, Institute of Medical Science, University of Tokyo, Japan.
Department of Pathobiological Sciences, School of Veterinary Medicine, University of Wisconsin-Madison.
出版信息
J Infect Dis. 2018 Mar 5;217(6):887-896. doi: 10.1093/infdis/jix606.
BACKGROUND
Treatment of immunocompromised, influenza virus-infected patients with the viral neuraminidase inhibitor oseltamivir often leads to the emergence of drug-resistant variants. Combination therapy with compounds that target different steps in the viral life cycle may improve treatment outcomes and reduce the emergence of drug-resistant variants.
METHODS
Here, we infected immunocompromised nude mice with an influenza A virus and treated them with neuraminidase (oseltamivir, laninamivir) or viral polymerase (favipiravir) inhibitors, or combinations thereof.
RESULTS
Combination therapy for 28 days increased survival times compared with monotherapy, but the animals died after treatment was terminated. Mono- and combination therapies did not consistently reduce lung virus titers. Prolonged viral replication led to the emergence of neuraminidase inhibitor-resistant variants, although viruses remained sensitive to favipiravir. Overall, favipiravir provided greater benefit than neuraminidase inhibitors.
CONCLUSIONS
Collectively, our data demonstrate that combination therapy in immunocompromised hosts increases survival times, but does not suppress the emergence of neuraminidase inhibitor-resistant variants.
背景
免疫功能低下、感染流感病毒的患者使用神经氨酸酶抑制剂奥司他韦治疗往往会导致耐药变异株的出现。联合使用针对病毒生命周期不同步骤的化合物进行治疗可能会改善治疗效果并减少耐药变异株的出现。
方法
在这里，我们用流感 A 病毒感染免疫功能低下的裸鼠，并使用神经氨酸酶（奥司他韦、拉尼米韦）或病毒聚合酶（法匹拉韦）抑制剂，或两者联合进行治疗。
结果
与单药治疗相比，28 天的联合治疗可延长存活时间，但在治疗终止后动物死亡。单药和联合治疗并不能始终降低肺部病毒滴度。病毒持续复制导致神经氨酸酶抑制剂耐药变异株的出现，尽管病毒对法匹拉韦仍保持敏感。总体而言，法匹拉韦的疗效优于神经氨酸酶抑制剂。
结论
综上所述，我们的数据表明，免疫功能低下宿主的联合治疗可延长存活时间，但不能抑制神经氨酸酶抑制剂耐药变异株的出现。
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